Malaria remains a significant health problem in tropical countries. Malaria due to Plasmodium (P) falicparum is the leading cause of death in African children less than 5 years of age. In holoendemic areas, such as sub-Saharan Africa, severe malarial anemia is the leading cause of death in children less than 3 years of age. In severely anemic children hemolysis is too bisk to be accounted for by the dystruction P falciparum infected red blood cells (RBCs) since only a small fraction of all red blood cells are infected. The anemia appears to be due to hemolysis of uninfected RBCs and to be immune-mediated. Severely anemic children with P falciparum infections often have a positive direct antiglobulin test (DAT) due to RBCs coated with IgG and complement. P falciparum infections also induces changes in RBC membranes. The expression of complement regulatory proteins CR1 (CD35) and decay accelerating factor (CD55) are decreased on RBCs from children with severe P falciparum anemia, but the expression of the RBC membrane inhibitor of reactive lysis (CD59) is increased. These results suggest that both autoantibodies and RBC membrane changes may contribute to the severe malaria anemia of childhood. The purpose of these studies is to investigate the role of the immune response and RBC membrane changes in malarial anemia. In collaborative studies with Dr Alan Magill, NIAID, we found the the culture of RBCs with P falicparum had no effect on the expression of antigens by uninfected RBCs. In collaborative studies with Dr. Trevor Jones, US Navy, malarial anemia is being studied in an aotus monkey model. Monkeys previously immunized by infection or vaccination to P falciparum protein EBA-175 and challenged with low levels of parasites became severely anemic despited level low levels of parsatemia. The DATs in the anemic animals were negative suggesting a role for the spleen and cellular immune response in the anemia. Future investigations will use the P falicparum vaccinated aotus monkeys as a model to further define the role of the immune system in severe malarial anemia.